Project Description As the population of individuals living beyond 65 years old increases, so does the incidence of neurocognitive diseases, leading to a decrease in quality of life. Thus, it is necessary to investigate mechanisms of cognitive aging and identify strategies for improving health outcomes in the elderly. The objective of this mentored training proposal is to determine the mechanisms behind the efficacy of a ketogenic diet for alleviating cognitive and neurometabolic decline in a rat model of old age. A ketogenic diet, which utilizes ketone bodies and fat as a fuel source, is particularly well suited for treating age-related dysfunction and disease. In fact, the decreases glucose metabolism and insulin dysregulation that are observed with advanced age and are a major risk factor for Alzheimer?s disease, are known to be reversed by a ketogenic diet. Specifically, the ketogenic diet bypasses glucose metabolism, enabling cells to utilize ketone bodies. Importantly, ketone metabolism has been shown to remain effective later in life relative to glucose metabolism capabilities. Based on preliminary data, the experiments in this proposal will test the central hypothesis that, by reducing the need for glucose metabolism, the ketogenic diet will improve hippocampal neuronal signaling, thereby improving behavioral performance. Furthermore, we will test the efficacy of direct application of ketone bodies systemically and intracranially into the hippocampus to aid in the determination of the mechanism s of efficacy of this treatment approach. This hypothesis will be tested with the following aims: 1) determine if ketosis can restore hippocampal circuits to improve behavioral performance; and 2) determine if ketone body administration attenuates age-related cognitive deficits. Under the first aim, a biconditional association task will be used to confirm the efficacy of a ketogenic diet, as well as direct application of ketone bodies, at restoring age-related cognitive decline. Neuronal activity during this behavior in brain regions providing inputs and outputs of the hippocampus will be quantified at the single cell level and correlated with behavioral performance to determine the degree to which age and ketosis affect neuronal communication. Under the second aim, direct hippocampal infusions of ketone bodies will be given prior to testing rats on a complex object discrimination task that is sensitive to aging, requires the hippocampus, and allows to a within-subjects assessment of performance. The proposed approach is innovative, because it represents a substantive departure from the status quo by integrating techniques from multiple levels of analysis, leading to a greater understanding of the effects of a ketogenic diet on age-related impairments. This work will be significant because it will support the development of therapeutic strategies for treating age-related decline in addition to several age and metabolic related disease states. Ultimately, such knowledge has the potential to improve quality of life and reduce the growing problem of both age-related cognitive and metabolic decline in the growing elderly population.